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15 October 1996 | Volume 125 Issue 8 | Pages 680-687
Our current understanding of sepsis and multiple organ dysfunction needs to be revised, as the uniformly negative results of new therapies for these disorders suggest.Previous theories for the pathogenesis of these conditions are incomplete; reasons for this include the following. First, the surrogate models that have been used to study these disorders are not analogous to the clinical situation. Second, patients who have less severe manifestations of these diseases are often overlooked. And third, patients' preexisting conditions have not been taken into account. Considerable new evidence indicates that, in addition to a massive proinflammatory reaction, a compensatory anti-inflammatory response contributes to the onset of these disorders. At a local site of injury or infection and during the initial appearance of pro- and anti-inflammatory mediators in the circulation, the beneficial effects of these mediators outweigh their harmful effects. Only when the balance between these two forces is lost do these mediators become harmful. Sequelae of an unbalanced systemic proinflammatory reaction include shock, transudation into organs, and defects in coagulation. An unbalanced systemic compensatory anti-inflammatory response can result in anergy and immunosuppression. The proinflammatory and anti-inflammatory forces may ultimately reinforce each other, creating a state of increasingly destructive immunologic dissonance.
It was only about 30 years ago that the acute respiratory distress syndrome was first described by Ashbaugh and colleagues [1, 2]. We had learned enough to be able to manage hemorrhagic shock without prompting renal shutdown [3], but too many patients still died of severe pulmonary complications. I was in Vietnam at that time, and watching so many young men die of what we then called "shock lung" or "Da Nang lung" was one of the formative experiences of my early career. In the 1960s, numerous other papers drew attention to various nonpulmonary causes of severe respiratory dysfunction, including abdominal surgery [4], peritonitis [5], and distant infections [6]. It became clear that pulmonary compromise could result from processes far removed from the lungs.
Slightly more than 20 years ago, the first descriptions of multiple organ failure appeared. In 1973, Tilney and associates [7] discussed three patients who had died of distal organ failure that followed ruptured aortic aneurysms. Baue [3] described "multiple, progressive, or sequential systems organ failure." These reports were followed by other classic papers, many of which attributed multiple organ failure to uncontrolled infection, especially gram-negative sepsis [8-11].
Ten years ago, it seemed as if we were finally beginning to understand the problem presented by sepsis and multiple organ failure. We started to realize that shock or infection alone did not cause distal organ dysfunction but rather that shock, infection, or other severe insults could set in motion an underlying reaction that would lead to widespread endothelial damage, edema resulting from increased vascular permeability, and impaired availability of oxygen [12]. Great hope arose when Ziegler and coworkers [13] showed that antiserum to endotoxin improved survival in patients with gram-negative sepsis.
Five years ago, we appeared to be entering a brave new world. Several of the mediators thought to cause the reaction underlying sepsis and multiple organ failure had been identified [14]. Clinical trials [15-29] were investigating various agents that, it was hoped, would downregulate these mediators. The ability to overcome sepsis and multiple organ failure seemed to be within our grasp.
The results of these trials were uniformly disappointing. Numerous studies were done with the following agents: monoclonal antibodies to endotoxin, methylprednisolone, monoclonal antibodies to tumor necrosis factor, dimeric tumor necrosis factor receptors, recombinant interleukin-1 receptor antagonist, and platelet-activating factor antagonists [30]. Agent after agent was found to have no effect—or worse, was found to increase mortality rates. Today, multiple organ failure affects as many as 40% of critically ill patients [31] and remains the leading cause of death in intensive care units [31, 32]. It is not surprising, therefore, that many physicians believe multiple organ failure to be an intractable problem. Although I understand their pessimism, I do not share it. I believe that we have made great strides in elucidating the pathogenesis of sepsis and multiple organ failure. It is true that the underlying inflammatory reaction is vastly more complicated than we had thought, and it is unlikely that a "magic bullet" will be found soon. However, by reexamining what we have learned and rethinking our assumptions, we can better understand how organ dysfunction develops and how we may someday be able to prevent it.
Problems with Previous Theories
Without question, a massive inflammatory reaction underlies both SIRS and MODS, as I will show. However, this reaction has both pro- and anti-inflammatory components. The anti-inflammatory reaction is often as great as, and sometimes greater than, the proinflammatory response.
To a large extent, the theories put forth to explain the development of SIRS (my own included) have not incorporated this anti-inflammatory reaction. Perhaps this was inevitable; many of the anti-inflammatory mediators have been discovered only recently. However, these theories have also often overstated the dangers presented by proinflammatory mediators. Although excessive levels of these mediators can cause problems, lower levels are beneficial—inflammation is required to combat pathogenic organisms and promote healing.
The overemphasis placed on proinflammatory mediators may have resulted in part from the surrogate models we have used to study SIRS and MODS: studies done in animals; experiments in which endotoxin, tumor necrosis factor, or another mediator was injected into human volunteers; and analyses of serum levels of proinflammatory mediators in patients with sepsis, burns, or other severe injuries. These studies may not accurately reflect what happens in critically ill patients.
For example, there is marked interspecies variation in cytokine release, which makes it difficult to extrapolate findings in animals to humans [34]. Experiments are done on healthy animals, and observation periods are generally short [35]. Human studies are done in healthy persons, the amount of stimulus injected is sublethal, and follow-up periods are brief [36]. In contrast, SIRS and MODS develop over time in severely ill or injured patients, who often have numerous preexisting disorders [14].
Analyses of serum levels are even more troublesome to interpret. Most immunoassays detect only circulating mediators, not mediators bound to cells or receptors [37-39]; thus, they may underestimate the effective amount of mediator acting at a cellular level. Bioassays, which measure the functional activity of cytokines, often lack specificity and may over-report amounts [40]. Furthermore, serum analyses are usually done sporadically (often once daily or less), yet mediator release is phasic. Most analyses have assumed that the presence of proinflammatory mediators is a direct result of the immediate insult (for example, a burn) and not a consequence of a preexisting condition. However, proinflammatory mediators are present in patients with widely varying disorders [41].
Range of Clinical Responses
Patients who develop sepsis or have extensive burns, massive traumatic injuries, or other severe insults can be grouped into several categories.
1. At one extreme are patients who show little evidence of a systemic reaction. Although recovery may be protracted because of the severity of the underlying illness, organ dysfunction rarely develops.
2. Next are patients who develop a mild form of SIRS and show some evidence of organ dysfunction early in the clinical course of disease. Dysfunction is usually limited to one or two organs and resolves rapidly—often within a day or two.
3. In other patients, a massive systemic inflammatory reaction develops rapidly after the initial insult. These patients often die of profound shock within a few days.
4. Still others have a less severe initial course of disease but deteriorate markedly several days or more after the original insult. Failure of one or more organs is common, and many of these patients die.
Most of the research done on SIRS and MODS has focused on the last two groups of patients. Clinical trials usually exclude patients who have mild symptoms of organ dysfunction or symptoms that last for less than 48 hours. Thus, these trials have excluded all patients in the first category and many of those in the second. However necessary this exclusion may have been to the design and conduct of those trials, it has skewed our perception of SIRS and MODS.
Some have suggested that evidence of organ dysfunction during the first 48 hours after insult reflects not the onset of MODS but rather the inciting event or incomplete resuscitation [42]. I believe that this distinction is artificial. Every severe insult to the body produces a response with pro- and anti-inflammatory components. But we must ask the following questions: Is the inflammatory response of an appropriate magnitude, and is it appropriately downregulated (as in the first two groups of patients)? Or does something go wrong (as in the second two groups)? By considering why SIRS and MODS do not develop in some patients, we can better understand why these disorders do arise in others.
A New Theory
The body is designed to compensate for any assault. Its defenses include macrophages and their products, such as tumor necrosis factor; interleukin-1, interleukin-6, and interleukin-8; neutrophils and the products of their degranulation; platelets and the coagulation factors formed on their surfaces; derivatives of arachidonic acid; T and B lymphocytes and their products; and many other substances [14]. How these agents interact is far from understood, but it is clear that they create a complex, often overlapping, network of interactions. Presented below is my explanation for how these agents work together to overcome a severe assault and, paradoxically, how they can cause SIRS and MODS (Figure 1). I admit that this explanation contains lacunae; too many facts remain unknown. However, I believe that this construct best explains the facts we do have. PERSPECTIVE
Immunologic Dissonance: A Continuing Evolution in Our Understanding of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS)
Fifty years ago, multiple organ failure was unheard of—we could not keep patients alive long enough for the sequential dysfunction of distal organs to develop. Patients with hemorrhagic shock died of blood loss or kidney failure. Severe infections were often fatal because antibiotic therapy was in its infancy.
The Systemic Inflammatory Response Syndrome and the Multiple Organ Dysfunction Syndrome
Five years ago, it became clear that the terms that we had been using to describe sepsis and organ dysfunction were no longer adequate. New terms were therefore developed by a consensus conference [33]. The term "systemic inflammatory response syndrome" (SIRS) is now used to describe the clinical syndrome previously called "sepsis"; the word "sepsis" is used only when the cause of SIRS is documented infection. "Multiple organ dysfunction syndrome" (MODS) replaces the term "multiple organ failure" because it stresses the continuum of organ dysfunction, not just its result.
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Stage 1: Local Response
Neither SIRS nor MODS develops de novo in the absence of an insult, such as a nidus of infection; traumatic injury (including a surgical wound); a severe burn; or pancreatitis. All of these insults (and others) have been shown to prompt release of various proinflammatory mediators in the microenvironment [14, 42, 43]: cytokines, eicosanoids, platelet-activating factor, and many more [14]. Any attempt to enumerate these other mediators would quickly become outdated because new agents are rapidly being discovered.
We do not yet know enough about how this local milieu operates; however, in the microenvironment, the beneficial effects of proinflammatory mediators outweigh their negative effects. These mediators create an elaborate web of reactions designed to limit new damage and ameliorate whatever damage has already occurred. They destroy damaged tissue; promote new tissue growth; and combat pathogenic organisms, neoplastic cells, and foreign antigens [39].
To ensure that the effects of proinflammatory mediators do not become destructive, the body soon launches an anti-inflammatory response. Included in this compensatory reaction are interleukin-4; interleukin-10; interleukin-11; soluble tumor necrosis factor receptors; interleukin-1 receptor antagonists; transforming growth factors; and other, as-yet-undiscovered, substances [26, 27, 39, 44]. The systemic effects of anti-inflammatory mediators are even less well understood than the effects of proinflammatory agents. However, anti-inflammatory agents are known to alter monocyte function, impair antigen-presenting activity, and reduce the ability of cells to produce proinflammatory cytokines [37]. Some of them have also been shown to downregulate their own production [44]. What other effects they may have remains to be determined, but there is no reason to suppose that they are any less pleiotropic than the proinflammatory mediators or that their effects are any less Janus-like. Local levels of pro- and anti-inflammatory mediators can be high—several orders of magnitude higher than those that are later found systemically [45-50].
Stage 2: Initial Systemic Response
If the original insult is sufficiently severe, proinflammatory and, later, anti-inflammatory mediators appear in the systemic circulation. (Mediator assays, although imprecise [as discussed above], currently remain the best way to gauge the severity of systemic pro- and anti-inflammatory reactions. Serologic markers of monocyte deactivation can also gauge the severity of the anti-inflammatory reaction.) How this occurs is not well understood; various mechanisms are probably involved. For example, in patients with severe infection, pathogens or foreign antigens may enter the bloodstream directly and incite the formation of more proinflammatory mediators. In patients with massive trauma, severe hemorrhage may prompt mediator synthesis [51, 52]. Systemic spillover may occur if a critical level of proinflammatory mediators is reached at the local site [45]. At this stage, the presence of these mediators in the circulation must be seen as part of the normal response to infection or injury. These agents signal that the microenvironment cannot control the initiating insult and that more help is needed. Proinflammatory mediators help recruit neutrophils, lymphocytes, platelets, and coagulation factors to the local site [14]. Eventually, they should stimulate a compensatory systemic anti-inflammatory response to downregulate the proinflammatory reaction. If all goes well, few (if any) important clinical signs and symptoms are produced, and organ dysfunction is rare.
Stage 3: Massive Systemic Inflammation
In some patients, regulation of the inflammatory response is lost, and a massive systemic reaction ensues. In most cases, this reaction is initially proinflammatory and produces clinical findings of SIRS, including hypotension, abnormal body temperature, and tachycardia. Various pathophysiologic changes underlie these findings. Progressive endothelial dysfunction occurs, leading to increased microvascular permeability and transudation into organs [53-57]. Platelet sludging blocks the microcirculation [58], causing maldistribution of blood flow and possibly ischemia, which in turn may cause reperfusion injury [59] and induction of heat shock protein [60]. The coagulation system is activated, and the protein C—protein S inhibitory pathway is impaired [61]. Dysregulation of vasodilatory and vasoconstrictive mechanisms produces profound vasodilation, which exacerbates transudation and maldistribution of blood flow [62, 63]. Often, the net result is severe shock, which further compromises blood flow to vital organs. Unless homeostasis is restored, organ dysfunction and, ultimately, failure ensue.
Overwhelming infection can develop in at least three ways [41]. First, the amount of proinflammatory mediators initially released is so great that compensatory anti-inflammatory mechanisms are overwhelmed. Second, the initial amount of proinflammatory mediators is not excessive, but the amount of anti-inflammatory mediators released is insufficient. Third, the balance between pro- and anti-inflammatory mediators, although initially appropriate, is lost if the inciting insult cannot be controlled or if a secondary insult intervenes [64].
Stage 4: Excessive Immunosuppression
Many patients with persistent or overwhelming inflammation die rapidly of shock. In those who survive, anti-inflammatory mechanisms may be able to control inflammation; in some patients, however, the compensatory reaction may be as excessive as the proinflammatory response, and immunosuppression ensues. Patients who never have the overwhelming proinflammatory response may also develop immunosuppression if release of anti-inflammatory mediators is excessive or if the balance between pro- and anti-inflammatory mediators is lost. This immunosuppression has been called "immune paralysis" by Randow and coworkers and Syrbe and associates [65, 66] and a "window of immunodeficiency" by Mills and colleagues [67]; I prefer to describe it as "the compensatory anti-inflammatory response syndrome" [68]. This syndrome explains the increased susceptibility to infection of patients with severe burns, hemorrhage, or trauma [69-73]; the anergy often found in patients with burns and trauma [73]; and perhaps the anergy found in patients with pancreatitis [74]. The immunosuppression seen in these circumstances has numerous causes. Patients often have increased numbers of monocytes, but the cells are characterized by fundamental functional disorders [75]. For example, a persistent decrease in HLA-DR and HLA-DQ antigen expression is seen [66], as is a diminished ability to form reactive oxygen species [76] and proinflammatory cytokines [37, 66, 75]. By suppressing monocytic MHC class II expression, interleukin-10 and transforming growth factor inhibit antigen-specific T-lymphocyte proliferation [77-80]. Transforming growth factor also reduces cytokine-induced macrophage activation [78-80]. T- and B-lymphocyte activity may be further altered by stress-induced glucocorticoid and catecholamine release or possibly by the administration of exogenous catecholamines, such as vasopressors and inotropes [81]. Serum factors capable of suppressing both T-lymphocyte proliferation and neutrophil chemotaxis have been found in patients with severe burns [82, 83], hemorrhage [84], and trauma [85]. Other agents that promote immunosuppression undoubtedly await discovery.
How immunosuppression resolves is not yet clear. Interleukin-10 eventually suppresses its own secretion [44], so it may be that the compensatory anti-inflammatory response is often self-limited. Colony-stimulating factors, particularly granulocyte-macrophage colony-stimulating factor, play a role by restimulating neutrophilic cytotoxicity [86]. However, evidence also indicates that patients who become immunosuppressed after trauma have a change in myeloid differentiation: Their bone marrow produces an increased proportion of a specific type of monocyte capable of producing increased levels of tumor necrosis factor, interleukin-1, and interleukin-6 [64, 87, 88]. Thus, persistent immunosuppression may be able to provoke a compensatory proinflammatory reaction.
Stage 5: Immunologic Dissonance
The final stage of MODS is reached when a patient develops what I have dubbed "immunologic dissonance," that is, a pathophysiologic response that is out of balance and inappropriate for the patient's biological needs. This can take various forms. In many patients, it results from persistent, overwhelming inflammation. Several studies [89-92] have shown that in patients with SIRS and MODS, persistently elevated levels of proinflammatory mediators are associated with increased mortality. In these patients, organ failure results from ongoing inflammation. Death ensues unless the inflammation can be downregulated. However, in some patients, persistent immunosuppression causes immunologic dissonance and increases the risk for death. In one study [66], patients whose HLA-DR antigen expression was less than 30% for more than 3 or 4 days had an 85% mortality rate.
In patients with persistent immunosuppression, the cause of organ failure may be paradoxical: The proinflammatory agents that originally caused organ dysfunction are the substances required for healing. Persistent immunosuppression may prevent the synthesis of enough of these agents to allow healing. Death will follow from organ failure or infection unless the immune system can recover.
Still other patients may oscillate between periods of severe inflammation and periods of immunosuppression (for example, patients who develop a secondary infection after a brief period of immunosuppression may be able to mount a second proinflammatory response, which then provokes another anti-inflammatory reaction, and so on). Evidence of this comes from studies showing that cytokine levels fluctuate widely for several weeks after burn injury [93-95].
It is even possible that some patients have persistently high levels of both pro- and anti-inflammatory mediators. Lehmann and coworkers [96] have shown that in patients with meningococcal disease, levels of interleukin-10 in serum and cerebrospinal fluid can remain high, even in the presence of elevated concentrations of tumor necrosis factor, interleukin-6, and interleukin-8. In fact, serum levels of interleukin-10 correlate positively with proinflammatory cytokine concentrations.
Patients with immunologic dissonance may be able to regain organ function if the body can recover its balance. If not, organ failure eventually occurs. Death at this stage can be prevented only if both pro- and anti-inflammatory forces are carefully titrated to restore homeostasis.
Why Does Dysregulation Occur?
At least two scenarios can plausibly explain why the imbalance between pro- and anti-inflammatory forces is lost. First, in some patients, the initial insult may be so severe that it is sufficient to prompt the development of SIRS and MODS. A considerable body of evidence supports the contention that massive infection or injury alone is enough to cause these disorders. Second, in many cases, patients may be "pre-primed" to develop SIRS and MODS. Epidemiologic studies show that SIRS is more likely to develop in patients who have preexisting severe illnesses (often defined as rapidly fatal or ultimately fatal illnesses [97]) than in healthy persons [98]. Patients with severe underlying illnesses are also more likely to have and to die of organ dysfunction [98, 99]. Patients known to be at increased risk for SIRS and MODS include those with metabolic, neoplastic, or immunodeficiency disorders; those who have received immunosuppressive therapy; those with diabetes or cirrhosis; and the elderly [14, 100].
Most of these conditions (including advanced age) are associated with abnormal cytokine levels [41]. It has been shown that the ability of a cell to synthesize pro- or anti-inflammatory mediators is influenced by its previous state of activation [87] as well as by the nearby hormonal milieu [14]. Thus, it is reasonable to hypothesize that patients with these conditions have been pre-primed to develop SIRS and MODS. For example, some patients may already have elevated levels of tumor necrosis factor, interleukin-1, or interleukin-6; the stress of an added infection might send these levels skyrocketing. Other patients may have "learned to live with" elevated cytokine levels and may be unable to produce adequate levels of these mediators in response to a new insult. Conversely, other patients may be pre-primed to release massive (or inadequate) levels of anti-inflammatory mediators. (It is also possible that some patients are protected from SIRS or MODS by similar mechanisms.) In patients with neoplastic disease, the situation may be even more complicated because some cancer cells are able to secrete cytokines [101]. Furthermore, it is not only cytokines that may be involved in pre-priming. T lymphocytes that recognize heat-shock proteins are part of the body's mechanism for eliminating host cells stressed by infection or other insults, but these lymphocytes may also play a pathogenetic role in rheumatoid arthritis [81].
The hypothesis of pre-priming underscores that a patient at risk for SIRS or MODS is not a tabula rasa. This fact may seem obvious, but I believe it has been overlooked. If we fail to take these preexisting conditions into account, we may miss an opportunity to refine our identification of patients at risk.
Conclusions
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may be useful for overcoming severe and persistent immunosuppression. Agents with both pro- and anti-inflammatory effects, such as ibuprofen, may ultimately prove to be the most helpful. Whatever the actual pathophysiology of SIRS and MODS turns out to be, it is likely to be enormously subtle and complex because it touches closely on basic biological functions that have undoubtedly evolved over eons.
Author and Article Information
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References
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